Project Summary/Abstract Liver cancer, including hepatocellular carcinoma (HCC) as well as metastatic tumors, is a major public health problem. For patients with unresectable liver cancer, thermal ablation, including radiofrequency ablation (RFA) and microwave ablation (MWA), is the current clinical standard of care; however, thermal ablation methods are limited by non-uniform and inconsistent treatment, leading to adverse side effects, local cancer recurrence, and decreased survival, severely limiting their clinical utility. Echo decorrelation imaging is a novel ultrasound approach that mitigates these problems by mapping ultrasound echo changes caused by tissue heating during thermal ablation. Research to date on echo decorrelation imaging has shown that this method reliably predicts ablation-induced cell death in vivo for rabbit and porcine liver tissue as well as VX2 liver cancer. Although echo decorrelation imaging is an extremely promising approach to thermal ablation monitoring and control, its translation to clinical practice will require validation of real-time, 3D ablation monitoring and control for human liver cancer ablation, including different tumor types (HCC and metastatic), as well as normal and abnormal human liver parenchyma (e.g., cirrhotic liver). Our central hypothesis for this study is that real-time monitoring and control by 3D echo decorrelation imaging will improve reliability of human liver tumor ablation. To test this hypothesis, we will implement 3D, real-time echo decorrelation imaging using a clinical ultrasound scanner and matrix array transducers, then validate the application of 3D echo decorrelation imaging to RFA and MWA. Methods for controlled ablation will be implemented for RFA using standard clinical electrodes and a clinical radiofrequency generator, with echo decorrelation serving as a treatment end point. To test the performance of clinical echo decorrelation imaging in human primary and metastatic cancer as well as diseased liver tissue, 3D echo decorrelation images will be formed from echo data recorded during open surgical RFA and percutaneous MWA procedures, then compared with follow-up contrast MRI and CT to assess prediction of ablated volume margins as well as local recurrence. Control of thermal ablation by 3D echo decorrelation imaging will first be studied in resected specimens of human metastatic liver cancer with normal liver tissue margins and specimens of cirrhotic human liver tissue, as well as in vivo swine liver. The study will then culminate in a treat-and-resect trial of echo decorrelation-controlled radiofrequency ablation in liver tumor patients, demonstrating the direct application of echo decorrelation imaging to improving clinical tumor ablation. This research will thus show feasibility for both effective prediction and real-time control of liver cancer ablation in human liver cancer and concomitant diseased liver tissue.